Title: “Synucleinopathy disorders: A tale of two neurotransmitters”.

Brainstem cholinergic nuclei, including the pedunculopontine nucleus (PPN) is important for a range of motor-related (e.g. gait) and cognitive functions (e.g. working memory, paying attention and planning). The role of these cholinergic neurons is becoming ever more apparent, as an instigator of some of the most pharmacologically challenging symptoms shown by patients of neurodegenerative diseases such as Parkinson’s disease (PD) and Lewy Body Dementia. These highlight the importance of studies aimed at understanding the causes of progressive degeneration of brainstem cholinergic neurons in neurodegenerative disease, to inform on efforts to rescue or slow down such degeneration. This represents a shift away from an overly dopaminergic focus as to causes of PD, which although important, may hamper important breakthroughs for successfully treating PD patients. In this talk, I will first discuss evidence from human and rodent studies that provide a rationale for studying cholinergic neurons in the context of neurodegenerative disease. This will provide the background for my group’s recent publications which created a rodent model which accurately reflects the brainstem cholinergic degeneration seen in PD-affected brains and then reported remarkably improved symptoms when only PPN cholinergic neurons were stimulated. In particular, we showed how structural-functional interactions between cholinergic-dopaminergic neurons might mitigate such a functional recover. I will also discuss our recent work using post-mortem PPNs from patients which followed a ‘single cell’ approach to discern the mitochondrial DNA mechanisms for the degeneration affecting this neuronal population. Hopefully, what I’m going to share will emphasize the importance of considering the human PPN as a heterogeneous structure, where precise targeting of its cholinergic neurons may provide profound therapeutic benefits to patients suffering from PD and related disorders.